This invention relates to a novel azapeptide derivative which is an antagonist of a receptor of neurokinin A (NKA) which is a tachykinin neuropeptide, and a salt thereof.
As transmitters of primary sensory nerves, there has been known the tachykinin family in which peptides have the C-terminal sequence (-Phe-X-Gly-Leu-Met-NH.sub.2). As said neuropeptides derived from mammals, there have been known neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) shown below (Kimura, S., et al., Proc. Japan Acd., 59B, pp. 101 to 104 (1983)).
NKA: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2 PA1 NKB: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2 PA1 SP: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 PA1 peptide I: [Tyr.sup.5, D-Trp.sup.6,8,9, Arg.sup.10 ]NKA(4-10) PA1 peptide II: [Tyr.sup.5, D-Trp.sup.6,8,9, Arg.sup.10 ]NKA(3-10) PA1 peptide III: Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH.sub.2 PA1 Dutta, A. S., et al., J. Chem. Soc., Perkin Trancs. 1 (1975) p. 712 PA1 Pinnen, F., et al., J. C. S. Perkin I (1993) pp. 819 to 824 (Boc-AzPhe-ONp)
These peptides exhibit excitation activities in central and peripheral nervous systems and exhibit analogous physiological activities such as constriction of smooth muscle (other than blood vessels), vasodilation, stimulation of endocrine and exocrine glands, exudation of plasma and immunity-inflammation in non-nervous tissues (Perow, B., Pharmacol. Rev., 35, p. 86 (1983), Yukio Takano, Taiyu Kamiya, Yakugaku Zasshi 108, p. 201 (1988), Maggio, J. M., Ann. Rev. Neurosci. 11, p. 13 (1989)).
It has been known that among them, NKA coexists with SP to exhibit potent activities of inducing contraction of respiratory smooth muscle in asthma, sthenia of secretion of respiratory mucosa and edema of respiratory mucosa (Lundberg, J. M., Arch. Int. Pharmacodyn. 303, p. 9 (1990), Barnes, P. J., Arch. Int. Pharmacodyn. 303, p. 67 (1990)). Also, NKA has been known as a substance having a potent constriction activity even in tissues other than respiratory tracts, for example, bladder, stomach and intestines. Thus, an antagonist of NKA has a possibility as an agent for curing bronchial asthma, gastrointestinal hyperkinesis and incontinence of urine.
As a compound having a NKA antagonistic activity, there have been reported peptide derivatives having 6 or more amino acid residues, such as
(Br. J. Pharmacol., 100, pp. 588 to 592 (1990), Japanese Provisional Patent Publication No. 17098/1991).
In general, it is estimated that a long chain peptide derivative is susceptible to enzymatic degradation and has poor absorption property and transition property in tissues. Thus, as compound which is more useful as a medicine, a compound having a low molecular weight and a compound having enzyme resistance have been demanded.